Nitric oxide donors and pharmaceutical compositions containing them

ABSTRACT

The present invention provides a compound containing at least one sulfhydryl group and at least one NO donor group, wherein said compound is a) a compound containing one or more sulfhydryl groups linked to at least one aromatic ring or a heteroaromatic ring with a nitrogen in the ring structure, which ring is substituted by one or more substituents bearing a terminal —ONO 2  group; b) a 5-membered ring heterocyclic compound containing a sulfur atom and a nitrogen atom, which ring is substituted by one or more substituents bearing a terminal —ONO 2  group; c) a 5-membered ring compound containing two conjugate S-atoms, which ring is linked to one or more substituents bearing a terminal—ONO 2  group; or d) a compound containing an acyclic —S—S group, linked to at least one aromatic ring or a heteroaromatic ring with a nitrogen in the ring structure, which ring is substituted by one or more substituents bearing a terminal —ONO 2  group. The present invention further provides pharmaceutical compositions comprising one or more of said compounds as an active ingredient.

CONTINUING APPLICATION DATA

[0001] This application is a Divisional Application of U.S. Ser. No.09/3831,303, filed Dec. 30, 1999, incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to nitric oxide donors containingat least one sulfhydryl group or a group capable of being convertedin-vivo to a sulfhydryl group, and at least one nitric oxide donorgroup. The novel compounds are effective substitutes for existingtolerance-inducing organic or inorganic nitric oxide donors.

BACKGROUND OF THE INVENTION

[0003] For over a century, the nitric oxide (NO) donor nitroglycerin(GTN) has been the mainstay in the treatment of angina and related heartdiseases. However, the existing mechanisms proposing the mediation ofGTN action by free NO, intracellular or extracellular S-nitrosothiolformation and subsequent activation of guanylyl cyclase (GC), as well asthose describing GTN tolerance, have become increasingly controversial.The phenomenon of tolerance to GTN, however, is of special clinicalimportance. In fact, early tolerance to the anti-anginal effects of thedrug is the major drawback of nitrate therapy, especially during acutemyocardial infarction. This is particularly important since alternativenon-tolerance inducing agents have not yet been developed tosuccessfully replace therapy with GTN.

[0004] Based on accumulating evidence, Applicant hypothesized that GTNmay directly interact with SH-group/s located on its target enzyme (GC)resulting in its S-nitrosylation and activation. However, subsequentauto-oxidation (disulfide formation) of these SH-groups renders theenzyme inert towards further reaction with GIN, resulting in tolerancedevelopment.

[0005] Additionally, evidence has recently been provided to support aninvolvement of the superoxide anion in the mechanism/s underlying GTNtolerance and cross-tolerance. According to these reports, increasedproduction of superoxide anion was found to accompany tolerancedevelopment to GTN in vascular tissue. Treatment with superoxidedismutase (SOD) significantly enhanced relaxation of control andtolerant vascular tissue to GTN and other exogenous and endogenousvasodilators.

[0006] While the precise mechanism for the vasorelaxant effect of GTN isunknown, a consensus exists regarding the primary involvement of cGMP inmediating the nitrate-induced relaxation. However, the roles ofsulfhydryl groups [reduced glutathione (GSH) and cysteine (Cys)] and ofvarious enzymes in the bioconversion of GTN and subsequent activation ofguanylyl cyclase (GC) leading to relaxation have become increasinglycontroversial. Cysteine was found to be the specific sulfhydryl requiredfor activation of soluble coronary arterial GC and to be the only one ofseveral sulfhydryls to react non-enzymatically with GTN at physiologicpH resulting in formation of S-nitrosocysteine. Since S-nitrosothiolswere shown to be potent activators of GC, S-nitrosocysteine/thiols wereproposed as the intracellular mediators of organic nitrate-inducedvasorelaxation. Additionally, N-acetylcysteine (NAC, an immediate donorof Cys thereby increasing GSH) was reported to potentiate GTN activityin vitro and in vivo. The enhanced reaction of thiols with GTN in plasmaand blood versus buffer suggested that activation of GC by GTN may bemediated via extracellular formation of S-nitrosothiol/s. In either case(intra- or extracellular S-nitrosothiol formation), this associationbetween sulfhydryls and GTN activity has long been recognized asevidence for the “thiol depletion hypothesis”. However, recent studiesby the Applicant and those of Boesgard et al. revealed a dissociationbetween tissue thiol content (measured as Cys and GSH) and nitratetolerance in vivo.

[0007] In vitro inhibitory studies provide indirect support for theinvolvement of enzymes in GTN bioactivation [glutathione S-transferase(GST) and cytochrome P-450 (P-450)]. However, in view of several otherreports suggesting the lack of any significant role of GST and P-450 inGTN bioactivation, the reduced bioactivation of GTN is unlikely to bethe main factor underlying nitrate tolerance in vivo. In fact, reducedcGMP production was also shown to follow exposure of vascularpreparation to direct NO-donors, for which no definitive metabolicpathway has been reported.

[0008] Furthermore, Applicant has recently presented in vivo evidenceexcluding the involvement of any particular metabolic pathway sincereduced cGMP was also shown to follow treatment with S-alkylating agentsin the absence of GTN.

[0009] Heart disease is the leading cause of death in Western societyand is rapidly approaching this leading position worldwide. Ischemicheart disease is the most common heart disease. For over a century,nitroglycerin and other organic nitrates have been used for thetreatment of various types of myocardial ischemia, including acutemyocardial infarction (AMI) and as adjuncts in the treatment of otherheart diseases (congestive heart failure and resistant hypertension).Chronic prophylaxis and acute treatment are necessary to preventcomplications of ischemic heart disease with potential fatal outcomes(˜25% death for AMI). Tolerance to the anti-ischemic effect of thesedrugs is, by far, the most serious drawback of therapy with currentlyavailable organic nitrates. The compounds proposed in this applicationconstitute a novel approach to overcome tolerance.

SUMMARY OF THE INVENTION

[0010] The present invention provides a compound containing at least onesulfhydryl group and at least one NO donor group, wherein said compoundis a) a compound containing one or more sulfhydryl groups linked to atleast one aromatic ring or a heteroaromatic ring with a nitrogen in thering structure, which ring is substituted by one or more substituentsbearing a terminal —ONO₂ group; b) a 5-membered ring heterocycliccompound containing a sulfur atom and a nitrogen atom, which ring issubstituted by one or more substituents bearing a terminal —ONO₂ group;c) a 5-membered ring compound containing two conjugate S-atoms, whichring is linked to one or more substituents bearing a terminal—ONO₂group; or d) a compound containing an acyclic —S—S group, linked to atleast one aromatic ring or a heteroaromatic ring with a nitrogen in thering structure, which ring is substituted by one or more substituentsbearing a terminal —ONO₂ group.

[0011] In one embodiment, the compound is:

[0012] In another embodiment, the compound is:

[0013] The present invention further provides a pharmaceuticalcomposition comprising a) as an active ingredient at least one compoundcontaining at least one sulfhydryl group and at least one NO donorgroup, wherein said compound is 1) a compound containing one or moresulfhydryl groups linked to at least one aromatic ring or aheteroaromatic ring with a nitrogen in the ring structure, which ring issubstituted by one or more substituents bearing a terminal —ONO₂ group;2) a 5-membered ring heterocyclic compound containing a sulfur atom anda nitrogen atom, which ring is substituted by one or more substituentsbearing a terminal —ONO₂ group; 3) a 5-membered ring compound containingtwo conjugate S-atoms, which ring is linked to one or more substituentsbearing a terminal —ONO₂ group; or 4) a compound containing an acyclic—S—S group, linked to at least one aromatic ring or a heteroaromaticring with a nitrogen in the ring structure, which ring is substituted byone or more substituents bearing a terminal —ONO₂ group; and b) apharmaceutically acceptable carrier.

[0014] In one embodiment, the active ingredient is:

[0015] In another embodiment, the active ingredient is:

DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0016] The present invention provides a compound containing at least onesulfhydryl group and at least one NO donor group, wherein said compoundis a) a compound containing one or more sulfhydryl groups linked to atleast one aromatic ring or a heteroaromatic ring with a nitrogen in thering structure, which ring is substituted by one or more substituentsbearing a terminal —ONO₂ group; b) a 5-membered ring heterocycliccompound containing a sulfur atom and a nitrogen atom, which ring issubstituted by one or more substituents bearing a terminal —ONO₂ group;c) a 5-membered ring compound containing two conjugate S-atoms, whichring is linked to one or more substituents bearing a terminal —ONO₂group; or d) a compound containing an acyclic —S—S group, linked to atleast one aromatic ring or a heteroaromatic ring with a nitrogen in thering structure, which ring is substituted by one or more substituentsbearing a terminal —ONO₂ group. The present invention further providespharmaceutical compositions comprising one or more of said compounds asan active ingredient.

[0017] The compounds are in vivo nitric oxide donors and they contain atleast one sulfhydryl group. As defined herein, a sulfhydryl group iseither present in the reduced —SH form, or is a group capable of beingconverted in-vivo to a sulfhydryl group. In one embodiment, thecompounds contain a sulfhydryl group in the reduced —SH form. In anotherembodiment, the compounds contain a group capable of being convertedin-vivo to a sulfhydryl group. Suitable groups which are capable ofbeing converted in-vivo to a sulfhydryl group are illustrated in thefollowing embodiments: In one embodiment, the sulfhydryl group is in theoxidized —S—S disulfide form. In another embodiment, the sulfhydryl ispresent in a separately protected form (acetyl, carbamyl or other). Inanother embodiment, the sulfhydryl is present as an atom in aheterocyclic compound. In cases where the compound contains twosulfhydryl groups, these can exist in the reduced (SH) or the oxidized(disulfide) form or in a protected form. However, each one of thecompounds can also be regarded as a parent pro-drug which is assumed toundergo metabolic reduction or cleavage to provide the free SH groupsin-vivo.

[0018] In one embodiment, the compound is a compound containing one ormore sulfhydryl groups linked to at least one aromatic ring or aheteroaromatic ring with a nitrogen in the ring structure, which ring issubstituted by one or more substituents bearing a terminal —ONO₂ group.In another embodiment, the compound is a 5-membered ring heterocycliccompound containing a sulfur atom and a nitrogen atom, which ring issubstituted by one or more substituents bearing a terminal —ONO₂ group.In another embodiment, the compound is a 5-membered ring compoundcontaining two conjugate S-atoms, which ring is linked to one or moresubstituents bearing a terminal —ONO₂ group. In another embodiment thecompound is a compound containing an acyclic —S—S group, linked to atleast one aromatic ring or a heteroaromatic ring with a nitrogen in thering structure, which ring is substituted by one or more substituentsbearing a terminal —ONO₂ group.

[0019] In accordance with an alternative embodiment of the presentinvention, the compound is a 6-membered ring compound containing twoconjugate S-atoms which is substituted by one or more —ONO₂ groups orlinked to one or more substituents bearing a terminal —ONO₂ group. Inanother embodiment the compound is a 6-membered ring compound containing2 conjugate S-atoms which is substituted by one or more —ONO₂ groups orlinked to one or more substituents bearing a terminal —ONO₂ group,wherein said 6-membered ring is conjugated to at least one carbocyclicaromatic nucleus or at least one pyridine nucleus. In anotherembodiment, the compound is a compound having an S—S group in an openconfiguration linked to one or more —ONO₂ groups or linked to one ormore substituents bearing a terminal —ONO₂ group.

[0020] In one embodiment, the compound is:

[0021] In another embodiment, the compound is:

[0022] All of the above compounds are such that they will undergo invivo metabolic cleavage to provide free —SH groups.

[0023] According to this invention, whenever a compound exists in theacid form, the term “acid” should also be understood to include thecorresponding acid halide, salts with pharmacologically acceptablealkali metal (including alkaline earth metal and ammonium bases), estersand amides. Moreover, the alcohol or the amines used to form thecorresponding ester and amides of the acid can also bear a nitrateester.

[0024] The present invention further provides a pharmaceuticalcomposition for the treatment of disorders where nitric oxide donors areindicated, comprising a) as an active ingredient at least one compoundcontaining at least one sulfhydryl group and at least one NO donorgroup, wherein said compound is 1) a compound containing one or moresulfhydryl groups linked to at least one aromatic ring or aheteroaromatic ring with a nitrogen in the ring structure, which ring issubstituted by one or more substituents bearing a terminal —ONO₂ group;2) a 5-membered ring heterocyclic compound containing a sulfur atom anda nitrogen atom, which ring is substituted by one or more substituentsbearing a terminal —ONO₂ group; 3) a 5-membered ring compound containingtwo conjugate S-atoms, which ring is linked to one or more substituentsbearing a terminal —ONO₂ group; or 4) a compound containing an acyclic—S—S group, linked to at least one aromatic ring or a heteroaromaticring with a nitrogen in the ring structure, which ring is substituted byone or more substituents bearing a terminal —ONO₂ group; and b) apharmaceutically acceptable carrier.

[0025] In one embodiment, the active ingredient is a compound containingone or more sulfhydryl groups linked to at least one aromatic ring or aheteroaromatic ring with a nitrogen in the ring structure, which ring issubstituted by one or more substituents bearing a terminal —ONO₂ group.In another embodiment, the active ingredient is a 5-membered ringheterocyclic compound containing a sulfur atom and a nitrogen atom,which ring is substituted by one or more substituents bearing a terminal—ONO₂ group. In another embodiment, the active ingredient is a5-membered ring compound containing two conjugate S-atoms, which ring islinked to one or more substituents bearing a terminal —ONO₂ group. hianother embodiment the active ingredient is a compound containing anacyclic —S—S group, linked to at least one aromatic ring or aheteroaromatic ring with a nitrogen in the ring structure, which ring issubstituted by one or more substituents bearing a terminal —ONO₂ group

[0026] In accordance with an alternative embodiment, the activeingredient is a 6-membered ring compound containing two conjugateS-atoms which is substituted by one or more —ONO₂ groups or linked toone or more substituents bearing a terminal —ONO₂ group. In anotherembodiment the active ingredient is a 6-membered ring compoundcontaining 2 conjugate S-atoms which is substituted by one or more —ONO₂groups or linked to one or more substituents bearing a terminal —ONO₂group, wherein said 6-membered ring is conjugated to at least onecarbocyclic aromatic nucleus or at least one pyridine nucleus. Inanother embodiment, the active ingredient is a compound having an S—Sgroup in an open configuration linked to one or more —ONO₂ groups orlinked to one or more substituents bearing a terminal —ONO₂ group.

[0027] In one embodiment, the active ingredient is

[0028] In another embodiment, the active ingredient is:

[0029] Because of their SH-content (radical scavenging and anti-oxidantproperties), these compounds may also be applied for other pathologies.Thus, considering their promising chemical and pharmacologicalcharacteristics and the ever-increasing demand for better therapy forheart diseases, significant potential exists for compounds of this typeto become the next generation of vasodilators. This is especially trueconcerning the considerable amount of recent evidence indicating theinvolvement of nitric oxide, reactive oxygen species and thiols in avariety of conditions, the pathogenesis of as well as the treatment forwhich have not been fully resolved. These include (but are not limitedto): atherosclerosis, pulmonary and systemic hypertension, asthma andother related respiratory diseases, trauma, shock, neurotoxicity,neurodegenerative and neurologic disorders, including those involvinglearning, memory, olfaction and nociception, Huntington, Alzheimer andParkinson's diseases, multiple sclerosis and convulsive (seizure)disorders, AIDS-related disorders (i.e. dementia), disorders of gastricacid and other secretory and peristaltic functions of the alimentarysystem, drug and disease-induced neuropathy and nephropathy,pathological and premature uterine contractions, cellular defenseimpairment, and insulin-resistance in glucose intolerance and diabetesmelfitus, pregnancy-induced hypertension, chemotaxis and phagocyticimpairment in immunological disorders, cerebrovascular diseases,aggregation disorders, penile erection and treatment of male impotence.

[0030] Although the exact mechanisms defining organic nitrates and othernitric oxide donors' action and tolerance are not completely elucidated,the primary roles of nitric oxide (being their first messenger) and cGMP(the second messenger) in mediating vasorelaxation are universallyaccepted. Applicant has demonstrated herein, utilizing example compounds1 to 6 from page 14, that, unlike currently available organic andinorganic nitrates, these compounds possess equipotent or ever superiorvasorelaxant activity. Moreover, using cGMP measurements both inextended periods of exposure to the drug when used, for example, innitroglycerin-equimolar dosing regimens for which tolerance to thecGMP-inducing activity of nitroglycerin has been documented under thesame experimental conditions (see table on page 30).

[0031] For the preparation of pharmaceutical compositions, the novelcompounds are mixed in the usual way with appropriate pharmaceuticalcarrier substances, aroma, flavoring and coloring materials and formed,for example, into tablets or dragees of immediate or sustained releaseor, with additions of appropriate adjuvants, for example water or an oilsuch as olive or other oil, are suspended or dispersed or dissolved.

[0032] The compounds or the pharmaceutical composition thereof can beadministered orally (including the sublingual and buccal routes) or viaan injectable form (including the subcutaneous, intramuscular,intraperitoneal and the parenteral routes). Other routes ofadministration such as aerosols and dennal preparations are also to beconsidered. As injection medium, water is preferably used which containsthe stabilizing agents, solubilizing agents and/or buffers usuallyutilized in the preparation of solutions for injection. Such additivesinclude, for example, tartarate and borate buffers, ethanol, ethyleneand propylene glycols, glycerol, dimethyl sulphoxide, complex formers(i.e., ethylenediamine tetraacetic acid), high molecular weight polymers(such as liquid polyethylene oxide) for viscosity regulation andpolyethylene derivatives of sorbit anhydrides. Solid carrier materialsinclude, for example, starch, lactose, mannitol, methyl cellulose, talc,highly dispersed silicic acid, high molecular weight polymers (i.e.,polyethylene glycol). Compositions suitable for oral administration (asdefined above) can, if necessary, contain flavoring and sweeteningagents.

[0033] The synthesis of the novel compounds was carried out utilizingconventional organic synthetic methods. The following examples are givenfor the purpose of illustrating the present invention:

EXAMPLE 1 trans-1,2-Dinitrato-4,5-dithiane (compound 1, page 14)

[0034] The compound was easily synthesized utilizing the commerciallyavailable precursor trans-1,2-dihydroxy-4,5-dithiane. 0.5 g of theprecursor was added portionwise to chilled (−5° C.) 1:1 mixture offuming nitric sulfuric acids. Upon completion of the addition, theice/salt bath was removed and the mixture brought to room temperature.This mixture was added dropwise to a cooled mixture of dry diethylether:acetonitrile:water (70:20:10) with vigorous stirring. The loweraqueous phase was separated and extracted twice with diethyl ether. Thecombined organic extracts were washed twice with water and once withcold 1% sodium carbonate solution. The organic layer was dried overmagnesium sulfate and evaporated to near dryness under reduced pressure.The residual oil was loaded on a silica column and separated afterelution with hexane. Evaporation under reduced pressure of the eluateyielded a yellowish oil (0.56 g) with analytical data consistent withthe structure of trans-1,2-dinitrato-4,5-dithiane.

EXAMPLE 2 2,2′-Dithiodiethanol-dinitrate (compound 2, page 14)

[0035] The compound was synthesized in a similar fashion to compound 1above using the commercially available precursor 2,2′-dithiodiethanol asthe starting material. The precursor was nitrated and separated as aboveyielding the title compound 2,2′-dithiodiethanol-dinitrate.

EXAMPLE 3 1,1-Diemethanol-dinitrate-3,4-dithiane (compound 3, page 14)

[0036] This compound was synthesized by bishydroxymethylation of diethylmalonate followed by thiolation of the hydroxyl groups (via the halideintermediate). The resulting 1,1-dicarboxy-3,4-dithiane was reduced byborane (catechol borane solution) to the corresponding1,1-diemethanol-3,4-dithiane. Direct nitration of this latterintermediate yielded the title compound1,1-diemethanol-dinitrate-3,4-dithiane.

EXAMPLE 4 1,1-Bisthiomethyl-3,4-dihydroxy-cyclohexane-dinitrate ester(compound 4 page 14)

[0037] This compound was synthesized by thiolation of the dichlorideintermediate of the commercially available1.1′-bishydroxymethyl-3-cyclohexene. Oxidation of the double bond eitherby hydrogen peroxide/asmium tetroxide to generate the cis-diol or by aperacid/formic acid mixture to generate the trans-diol followed bynitration of the diol will generate the corresponding (cis or trans)form of the title compound.

EXAMPLE 5 Thioctyl alcohol nitrate ester (compound 5, page 14)

[0038] This compound was synthesized in a high yield process utilizingthioctic acid as the precursor. Following reduction of the acid (or itsmethyl or ethyl ester) by catechol borane solution, the resultingthioctyl alcohol was separated and mitrated as described above to yieldthe title compound.

EXAMPLE 6 1,2-Dihydroxy-dinitrate-6,8-dithiane (compound 6, page 14)

[0039] 2-Hydroxy lipoic (thioctic) acid was synthesized from thiocticacid via the 2-bromo derivative. This intermediate was reduced viaborane to yield the direct precursor 1,2-dihydroxy-6,8-dithiane which,upon nitration as described above, yielded the title compound.

Experimental Report

[0040] Representative for the new compounds, the vasorelaxant activities(measured as the ability of the tested drug to induce an increase invascular cGMP) of the example compounds 1 to 6 were determined andcompared to activity of nitroglycerin under the same experimentalconditions following single and sustained exposure of rats to thecompound.

[0041] For this purpose the compound to be tested was administered, ineach case, to 8 male Sprague-Dawley rats (300-400 g) before and after an18 hr continuous intravenous infusion of the compound. The 18 hrcontinuous infusion period was determined based on existing datademonstrating the development of tolerance to the drug effect in thecase of nitroglycerin. The existence of tolerance to the drug isdemonstrated by the inability of the drug to attain 50% or more of thecGMP values measured in the vascular tissue after dosing of the drug topreciously treated animals as compared to controls (non-treated orvehicle-treated animals). After drug administration (i.v. push), the ratwas sacrificed, the aorta immediately removed and processed for cGMPmeasurement as has been described in detail by us. All of the tested newcompounds were utilized in nitroglycerin equimolar doses, either beforeof after the “tolerance” induction period.

[0042] The following table summarizes the results obtained followingadministration of either nitroglycerin or the tested compounds beforeand after an 18 hr continuous exposure to the same compound: cGMZP(pmol/g tissue) Tested Compound Pre-infusion Post-infusion Nitroglycerin153 ± 13  68 ± 9** Compound 1 196 ± 14 189 ± 13* Compound 2 169 ± 12 174± 13* Compound 3 171 ± 14 174 ± 16* Compound 4 149 ± 11 169 ± 13*Compound 5 123 ± 13 113 ± 11* Compound 6 193 ± 17 179 ± 12*

[0043] Besides their expected superior vasorelaxant activity, theseresults clearly demonstrate that whereas tolerance to the cGMP-inducingactivity of nitroglycerin developed early (18 hr) following itscontinuous in vivo administration, no tolerance was observed to thecGMP-increasing effects of the novel compounds under the sameexperimental conditions used for the induction of in vivo tolerance. Infact, Applicant shows in preliminary results that no tolerance to thiscGMP-inducing effect of these novel SH-containing-NO-donors developseven after exposure of the animals to the compounds for extended periodsof time (i.e., not even after 168 hr of continuous intravenousinfusions).

[0044] It will be understood that the compounds shown demonstrate theprinciple upon which this invention is based. Thus, the specificationand examples given in this application are illustrative but notlimitative of the present invention and embodiments within the spiritand scope of the invention will suggest themselves to those skilled inthe art. Rather, the scope of the invention is defined by the claimswhich follow.

What is claimed is:
 1. A compound containing at least one sulfhydrylgroup and at least one NO donor group, wherein said compound is: acompound containing one or more sulfhydryl groups linked to at least onearomatic ring or a heteroaromatic ring with a nitrogen in the ringstructure, which ring is substituted by one or more substituents bearinga terminal —ONO₂ group; a 5-membered ring heterocyclic compoundcontaining a sulfur atom and a nitrogen atom, which ring is substitutedby one or more substituents bearing a terminal —ONO₂ group; a 5-memberedring compound containing two conjugate S-atoms, which ring is linked toone or more substituents bearing a terminal —ONO₂ group; or a compoundcontaining an acyclic —S—S group, linked to at least one aromatic ringor a heteroaromatic ring with a nitrogen in the ring structure, whichring is substituted by one or more substituents bearing a terminal —ONO₂group.
 2. A compound according to claim 1, wherein said compound is:


3. A compound according to claim 1, wherein said compound is:


4. A pharmaceutical composition comprising a) as an active ingredient atleast one compound containing at least one sulfhydryl group and at leastone NO donor group, wherein said compound is: a compound containing oneor more sulfhydryl groups linked to at least one aromatic ring or aheteroaromatic ring with a nitrogen in the ring structure, which ring issubstituted by one or more substituents bearing a terminal —ONO₂ group;a 5-membered ring heterocyclic compound containing a sulfur atom and anitrogen atom, which ring is substituted by one or more substituentsbearing a terminal —ONO₂ group; a 5-membered ring compound containingtwo conjugate S-atoms, which ring is linked to one or more substituentsbearing a terminal —ONO₂ group; or a compound containing an acyclic —S—Sgroup, linked to at least one aromatic ring or a heteroaromatic ringwith a nitrogen in the ring structure, which ring is substituted by oneor more substituents bearing a terminal —ONO₂ group; and b) apharmaceutically acceptable carrier.
 5. A composition according to claim4 wherein the active ingredient is:


6. A composition according to claim 4, wherein the active ingredient is: